Solid oral formulations for combination therapy

Abstract

Multifunctional, single, bilayer, and trilayer coated tablets for combination therapy are formed wherein the bioactive agents responsible for the therapeutic multifunctionality are present as a combination of a gastric acid-reducing agent, such as omeprazole and ranitidine, and at least one analgesic/anti-inflammatory agent, such as acetaminophen, naproxen sodium, ibuprofen, tolmetin, and aspirin.

1 . A combination therapy coated tablet, comprising:
 (a) a therapeutically effective dose of a non-steroidal anti-inflammatory drug (NSAID);   (b) a therapeutically effective dose of an agent for reducing gastric acid secretion;   (c) a thermoplastic hydrophilic polymer;   (d) a microparticular excipient; and   (e) a cellulosic enteric coating.   
     
     
         2 . A combination therapy coated tablet as in  claim 1  wherein the NSAID is selected from the group consisting of naproxen sodium, ibuprofen, and tolmetin, the agent for reducing gastric acid secretion comprises ranitidine, the thermoplastic hydrophilic polymer comprises a solid polyethylene glycol, the microparticular excipient comprises microcrystalline cellulose, and the enteric coating comprises hydroxypropyl cellulose. 
     
     
         3 . A combination therapy coated tablet, comprising:
 (a) a therapeutically effective dose of an analgesic drug;   (b) a therapeutically effective dose of an agent for reducing gastric acid secretion;   (c) a thermoplastic hydrophilic polymer;   (d) a microparticular excipient; and   (e) a cellulosic enteric coating.   
     
     
         4 . A combination therapy coated tablet as in  claim 3  wherein the analgesic drug comprises aspirin, the agent for reducing gastric acid secretion comprises omeprazole, the thermoplastic hydrophilic polymer comprises a solid polyethylene glycol, the microparticular excipient comprises microcrystalline cellulose, and the enteric coating comprises hydroxypropyl methyl cellulose phthalate. 
     
     
         5 . A combination therapy coated bilayer tablet comprising:
 (a) a first layer comprising a therapeutically effective dose of acetaminophen dispersed in a water-soluble thermoplastic polymer; the first layer providing for the delayed release of the acetaminophen;   (b) a second layer comprising a therapeutically effective dose of a non-steroidal anti-inflammatory drug and a therapeutically effective dose of an agent for reducing gastric acid secretion, the second layer providing for the fast release of the non-steroidal anti-inflammatory drug and the agent for reducing gastric acid secretion; and   (c) a polymeric enteric coating.   
     
     
         6 . A combination therapy coated bilayer tablet as in  claim 5  wherein the water-soluble thermoplastic polymer comprises a solid polyethylene glycol, the non-steroidal anti-inflammatory drug comprises naproxen sodium, the agent for reducing gastric acid secretion comprises ranitidine and the enteric coating comprises hydroxypropyl cellulose. 
     
     
         7 . A method for the preparation of the bilayer tablet as in  claim 6  comprising the steps of:
 (a) dispersing acetaminophen in molten polyethylene glycol;   (b) cooling the acetaminophen/polyethylene glycol system and grinding;   (c) pressing the ground acetaminophen/polyethylene glycol system at room temperature and a pressure of less than 500 lbs;   (d) opening the mold and placing a mixture of the non-steroidal anti-inflammatory drug and the agent for reducing gastric secretion over the formed acetaminophen/polyethylene glycol first layer;   (e) pressing the combined system at room temperature and a pressure of 500 to 1000 lbs;   (f) removing the bilayer tablet from the mold;   (g) dip-coating it in a solution of hydroxypropyl cellulose in 2-propanol; and   (h) allowing the coated tablet to air dry.   
     
     
         8 . A combination therapy coated bilayer tablet comprising:
 a first layer comprising a therapeutically effective dose of an analgesic drug and a second layer comprising a therapeutically effective dose of an agent for reducing gastric acid secretion wherein each layer contains microparticular polymeric excipients and hydrophilic polymeric excipients.   
     
     
         9 . A combination therapy coated bilayer tablet as in  claim 8  wherein the analgesic drug comprises aspirin, the acid reducing agent comprises omeprazole, the hydrophilic polymeric excipient comprises a solid polyethylene glycol, and the microparticular excipient comprises microcrystalline cellulose, and further wherein the entire tablet is coated with a hydroxypropyl methyl cellulose phthalate. 
     
     
         10 . A combination therapy coated trilayer tablet comprising:
 a first layer comprising a therapeutically effective dose of an analgesic drug, microparticular polymeric excipients, and hydrophilic polymeric excipients, a second layer comprising a therapeutically effective dose of an agent for reducing gastric acid secretion, microparticular polymeric excipients, and hydrophilic polymeric excipients, and a third, drug-free layer of a solid, water-soluble polymer adjoining the first and second drug-containing layers.   
     
     
         11 . A combination therapy coated trilayer tablet as in  claim 10  wherein the analgesic drug comprises aspirin, the agent for reducing gastric acid secretion comprises omeprazole, the microparticular excipient comprises microcrystalline cellulose, the hydrophilic polymeric excipient comprises a polyethylene glycol solid, and the water-soluble polymer comprises a polyethylene glycol, and further wherein the entire tablet is coated with a hydroxypropyl methyl cellulose phthalate. 
     
     
         12 . A combination therapy coated trilayer tablet as in  claim 11  wherein the agent for reducing gastric acid secretion comprises the magnesium salt of omeprazole. 
     
     
         13 . A combination therapy coated trilayer tablet comprising:
 a first layer comprising a therapeutically effective dose of an analgesic drug mixed with microparticular and hydrophilic polymeric excipients, a second layer comprising a mixture of microparticular and hydrophilic polymeric excipients, an inorganic base and a therapeutically effective dose of an agent for reducing gastric acid secretion and a third drug-free layer of a solid water-soluble polymer adjoining the first and second drug-containing layers.   
     
     
         14 . A combination therapy coated trilayer tablet as in  claim 13  wherein the analgesic drug comprises aspirin, the agent for reducing acid secretion comprises omeprazole, the microparticular excipient comprises microcrystalline cellulose, the hydrophilic excipient comprises a polyethylene glycol, the solid water-soluble polymer comprises a polyethylene glycol, and the inorganic base comprises sodium bicarbonate, and further wherein the entire tablet is coated with a hydroxypropyl methyl cellulose phthalate.